Synthesis of the novel chiral 1,3-amino alcohol 8-N,N-bis(ferrocenylmethyl)amino-menthol and its use as catalyst in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(02)00063-0

Optically active 8-N,N-bis(ferrocenylmethyl)aminomenthol 5, obtained by condensation of (-)-aminomenthol with ferrocenecarboxaldehyde followed by N-alkylation with (ferrocenylmethyl)trimethylammonium iodide and further reduction, was found to catalyze (5 mol%) the enantioselective ethylation of aromatic, aliphatic and organometallic aldehydes to secondary alcohols with high enantioselectivities (up to 95%) at room temperature.

Full text of DOI:10.1016/S0957-4166(02)00063-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 5–8
Synthesis of the novel chiral 1,3-amino alcohol
8
-N,N-bis(ferrocenylmethyl)amino-menthol and its use as catalyst
in the enantioselective addition of diethylzinc to aldehydes
a
a,
a
b
b
Mar ´ı a J. Vilaplana, Pedro Molina, * Antonio Arques, Celia Andr e´ s and Rafael Pedrosa
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Qu ´ı mica, Universidad de Murcia, Campus de Espinardo, E-30100 Murcia,
Spain
b
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Universidad de Valladolid, E-47011 Valladolid, Spain
Received 10 December 2001; accepted 6 February 2002
Abstract—Optically active 8-N,N-bis(ferrocenylmethyl)aminomenthol 5, obtained by condensation of (−)-aminomenthol with
ferrocenecarboxaldehyde followed by N-alkylation with (ferrocenylmethyl)trimethylammonium iodide and further reduction, was
found to catalyze (5 mol%) the enantioselective ethylation of aromatic, aliphatic and organometallic aldehydes to secondary
alcohols with high enantioselectivities (up to 95%) at room temperature. © 2002 Elsevier Science Ltd. All rights reserved.
Catalytic asymmetric carbonꢀcarbon bond formation is
the catalyst and facilitating work-up procedures are still
challenging endeavors.
one of the most active research areas in organic synthe-
sis. In this field, the asymmetric addition of diethylzinc
1
(
Et Zn) to aldehydes has attracted much attention.
The synthesis of our ligands was accomplished in high
yields starting from the commercially available fer-
rocenecarboxaldehyde and (−)-8-aminomenthol 1 (5c-
methyl-2t-(1-methyl-1-aminoethyl)-cyclohexan-1r-ol),
2
These reactions require a compound coordinating the
metal ion to enhance the nucleophilicity of the
organometallic reagent, since the uncoordinated
organozinc species is virtually unreactive to the alde-
hyde. Due to the enhanced reactivity of the complexed
reagent, even a catalytic amount of the ligand can be2
used. A variety of chiral catalysts such as chiral diols,
10
easily prepared from (+)-pulegone. Condensation of
ferrocenecarboxaldehyde with (−)-8-aminomenthol 1
leads to 11the chiral 2-ferrocenyl-octahydro-1,3-
benzoxazine 2 in 98% yield as a single diastereomer,
with equatorial orientation of the ferrocenyl substituent
3
4
5
b-amino alcohols, diamines and amino thiols have
been developed for this reaction, which shows excellent
enantioselection for both aromatic and aliphatic
substrates.
12
as revealed by the X-ray structure (Fig. 1). N-Alkyl-
ation of 2 was achieved by reaction with (ferrocenyl-
13
methyl) trimethyl ammonium iodide or benzyl bro-
mide in refluxing acetonitrile in the presence of
potassium carbonate to give 3a and 3b in 98 and 92%
yields, respectively. Compounds 3 underwent ring open-
ing of the 1,3-oxazine ring either by the action of
In this context, ferrocenylamino alcohols were reported
to have the ability to catalyze the asymmetric addition
1
b,6
of dialkylzinc reagents to aldehydes.
ferrocene derivatives possessing either planar and cen-
Among them,
1
4
methylmagnesium bromide at room temperature to
7
8
tral chirality or only planar chirality induced high
enantioselectivities, while ferrocenylamino alcohols pos-
sessing only central chirality were found to provide
give 4 in 86–92% yields or with DIBAL-H in toluene at
15
0°C to afford 5 in 93% yield (Scheme 1).
9
modest degrees of induction. Despite the approaches
used, the design and development of a cost-effective
catalyst, lowering the concentration and/or recovering
With these ligands in hand, we first examined the
enantioselective addition of diethylzinc to benzalde-
hyde, taken as a benchmark reaction, in the presence of
5
mol% of the chiral ligands 3–5 in toluene at room
temperature. Compounds 3–5 proved ineffective cata-
lysts for the ethylation of benzaldehyde even after
extended reaction times. With the expectation that an
additive would alter the nature of the zinc species in
*
0
Corresponding author. Tel.: 34-968-367496; fax: 34-968-364149;
e-mail: pmolina@um.es
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00063-0

6
M. J. Vilaplana et al. / Tetrahedron: Asymmetry 13 (2002) 5–8
enantioselection
organometallic substrates (Scheme 2). As can be seen
in Table 1, the yields of the alcohols were in the range
for
aromatic,
6
aliphatic
and
1
7
0–90% with e.e.s of 60–95%.
The chiral ligand 5 was recovered in excellent yield (ca.
4%) from the reaction mixture by silica gel chromatog-
9
raphy and re-used without any loss of enantiomeric
purity of the product.
It has been established that in the presence of
methanol, the related ligand, 3-exo(dimethylamino)-
isoborneol serves as an effective chiral catalyst for the
addition of diethylzinc to a variety of aryl–alkyl
17
and diaryl ketones. In this context, the addition of
Figure 1. ORTEP drawing of compound 2.
Scheme 2.
solution, we pre-treated the catalysts with methylmag-
nesium bromide. We were pleased to discover that
pretreatment of the catalysts 3 and 4 with 1 mol% of
methylmagnesium bromide afforded (S)-1-phenyl-1-
propanol in excellent yield (93%) although with moder-
ate e.e. (50%). Taking into account the fact that the
yield and e.e. in both reactions are identical and the
fact that 3 is converted into 4 by the action of methyl-
magnesium bromide, we think that the active species as
catalyst in both reactions is derived from the ligand 4.
However, when the enantiopure amino alcohol 5 was
used, the result was very promising and optically active
Table 1. Enantioselective addition of diethylzinc to alde-
hydes in the presence of chiral catalysts 5
Entry Aldehyde
Yielda,b (%) E.e. (%)b Configurationc
1
2
3
4
5
6
7
Ph-CHO
p-MeOC H CHO
87
65
76
95
71
95
90
68
77
73
S
S
S
R
S
S
R
6
4
p-ClC H CHO
6
4
C H CH=CHCHO 78
6
5
CH
CH=CHCHO 70
3
CH (CH ) CHO
73
90
3
2 4
FecCHO
1
9
-phenyl-1-propanol was obtained in 87% yield and
5% e.e., with preferred formation of the (S)-isomer.
a
Yields of isolated products. The reactions were performed in dry
toluene during 20 h under nitrogen with 5 mol% catalyst using
aldehyde and diethylzinc in 1:2 ratio at room temperature.
Determined by HPLC on Cyclobond I 2000, Astec (eluent hexane/
isopropanol 90/10, flow rate 0.7 mL/min).
This finding prompted us to evaluate the catalytic
capability of the new catalyst with other aldehydes. The
results showed that the chiral amino alcohol 5 was
efficient in this asymmetric reaction, giving reasonable
b
c
Determined from the comparison of the sign of the specific rotation
with the literature data.
Scheme 1.

M. J. Vilaplana et al. / Tetrahedron: Asymmetry 13 (2002) 5–8
7
diethylzinc to benzaldehyde in the presence of 5 mol%
Iovel, I.; Oehme, G.; Lukevics, E. Appl. Organomet.
Chem. 1998, 12, 469–474; (q) Cho, B. T.; Chun, Y. S.
Tetrahedron: Asymmetry 1998, 9, 1489–1492; (r) Kotsuki,
H.; Hayakawa, H.; Tateishi, H.; Wakao, M.; Shiro, M.
Tetrahedron: Asymmetry 1998, 9, 3203–3212; (s) Shi, M.;
Satoh, Y.; Masaki, Y. J. Chem. Soc., Perkin Trans. 1
1998, 2547–2552; (t) Reddy, K. S.; Sola, L.; Moyano, A.;
Pericas, M. A.; Riera, A. J. Org. Chem. 1999, 64, 3969–
3974; (u) Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi, M.
C. K.; Yang, L.; Wong, K.-Y. Tetrahedron: Asymmetry
of the ligand 5 and 1.5 equiv. of methanol provided
(
S)-1-phenyl-1-propanol in 85% yield albeit in 40% e.e.
In summary, we have clearly demonstrated that the
enantiopure ferrocene–substituted 1,3-amino alcohol 5
can act as an efficient promoter in the enantioselective
addition of diethylzinc to a range of aldehydes. The
main distinctive feature of this ligand is represented by
an economical and simple asymmetric synthesis, involv-
ing cheap starting materials, which combine to give a
more complex compound without side products.
1999, 10, 133–138; (v) Zhang, H.; Chan, K. S. J. Chem.
Soc., Perkin Trans. 1 1999, 381–382.
4
. (a) Rosini, C.; Franzini, L.; Iuliano, A.; Pini, D.; Sal-
vadori, P. Tetrahedron: Asymmetry 1991, 2, 363–366; (b)
Conti, S.; Falorni, M.; Giacomeili, G.; Soccolini, F.
Tetrahedron 1992, 48, 8993–9000; (c) Urabe, H.;
Yamakawa, T.; Sato, F. Tetrahedron: Asymmetry 1992, 3,
Acknowledgements
5
–8; (d) Asami, M.; Usui, K.; Higuchi, S.; Inoue, S.
We thank the Direcci o´ n General de Investigaci o´ n
Chem. Lett. 1994, 297–298; (e) Nowotny, S.; Vettel, S.;
Knochel, P. Tetrahedron Lett. 1994, 35, 4539–4540; (f)
Vyskocil, S.; Jaracz, S.; Smreina, M.; Sticha, M.; Hanus,
V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63,
(
MCYT, Spain), project number BQU2001-0014 for
financial support.
7
727–7737; (g) Hwang, C.-D.; Uang, B.-J. Tetrahedron:
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5, 4168–4175; (b) Hayashi, M.; Kaneko, T.; Oguni, N. J.
Chem. Soc., Trans. 1 1991, 25–28; (c) Bolm, C.; Ewald,
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Kimura, K.; Sugiyama, E.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1992, 33, 3147–3150; (e) Behnen, W.;
Mehler, T.; Martens, J. Tetrahedron: Asymmetry 1993, 4,
1
1
0. Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315–3325.
1. Spectral data for compound 2: [h] =−28.0 (c 1.5,
20
D
CHCl ), mp 105–7°C, IR (Nujol), 3318, 3094, 3073, 1209,
3
1
413–1416; (f) Wallbaum, S.; Martens, J. Tetrahedron:
1145, 1107, 1059, 1011, 926, 830, 776. MS (GC-EI), 368
Asymmetry 1993, 4, 637–640; (g) Jones, G. B.; Heaton, S.
B. Tetrahedron: Asymmetry 1993, 4, 261–272; (h) Andr e´ s,
J. M.; Mart ´ı nez, M. A.; Pedrosa, R.; P e´ rez-Encabo, A.
Tetrahedron: Asymmetry 1994, 5, 67–72; (i) Watanabe,
M.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1994, 837–
+
+
(
(
(
M +1, 28), 367 (M , 100), 301 (6), 255 (23), 254 (47), 214
45), 213 (89), 199 (17), 186 (77), 121 (45). H NMR
CDCl , 300 MHz): 5.06 (s br, 1H; H2), 4.32–4.29 (m,
1
3
1
H; H2%/H5%), 4.28–4.25 (m, 1H; H2%/H5%), 4.15 (s, 5H;
3
Cp), 4.10–4.05 (m, 2H; H3%/H4%), 3.50 (ddd, 1H, J=10.8,
3
3
2
8
42; (j) Watanabe, M.; Soai, K. J. Chem. Soc., Perkin
J=9.6 Hz, J=4.2 Hz; H8a), 1.97 (dddd, 1H, J=12.3
3
3
3
Trans. 1 1994, 3125–3128; (k) Ishizaki, M.; Fujita, K.;
Shimamoto, M.; Hoshino, O. Tetrahedron: Asymmetry
Hz, J=5.4 Hz, J=3.9 Hz, J=1.8 Hz; H8 ), 1.78–1.62
(m, 2H; H6 , H5 ), 1.56–1.44 (m, 1H; H7), 1.13 (s, 3H;
Me -C4)), 1.11 (s, 3H; Me -C4)), 0.94 (s, 3H, J=6.6
eq
ec
eq
3
1
994, 5, 411–424; (l) De Vries, A. H. M.; Jansen, J. F. G.
ax eq
A.; Feringa, B. L. Tetrahedron 1994, 50, 4479–4491; (m)
Fujisawa, T.; Itoh, S.; Shimizu, M. Chem. Lett. 1994, 10,
Hz; Me-C7), 1.20–0.80 (m, 4H; H4a, H5 , H6 , H8 ).
ax ax ax
13
The N-H proton was not observed. C NMR (CDCl , 75
3
1
777–1780; (n) Di Simone, B.; Savoia, D.; Tagliavini, E.;
Umani-Ronchi, A. Tetrahedron: Asymmetry 1995, 6, 301–
06; (o) Sola, L.; Reddy, K. S.; Vidal-Ferran, A.; Moy-
MHz): 89.61 (C1%), 80.42 (C2), 74.86 (C8a), 68.70 (Cp),
67.45 (CH:Fc), 67.39 (CH:Fc), 66.60 (CH:Fc), 66.51
(CH:Fc), 51.86 (C4a), 51.28 (C4), 41.87 (C8), 35.10 (C6),
3
ano, A.; Pericas, M. A.; Riera, A.; Alvarez-Larena, A.;
31.39 (C7), 30.06 (Me -C4), 25.58 (C5), 22.30 (Me-C7),
eq
Piniella, J.-F. J. Org. Chem. 1998, 63, 7078–7082; (p)
19.78 (Me -C4).
ax

8
M. J. Vilaplana et al. / Tetrahedron: Asymmetry 13 (2002) 5–8
1
2. X-Ray data for compound 2. The crystal was mounted
with glue and transferred to the diffractometer (Siemens
P4). The structures were solved by the heavy atom
68.32 (Cp), 67.02 (CH:Fc), 61.27 (M CN), 47.76 (C),
2
47.23 (CH Fc), 45.38 (CH Fc), 44.73 (C6), 35.09 (C4),
2
2
30.77 (C5), 25.81 (C3), 22.01 (Me), 21.52 (Me), 19.99
(Me).
2
method and refined anisotropically on F (program
SHELX-93). Crystal data: C H FeNO, M=367.30,
16. General experimental procedure: To a degassed solution
of amino alcohol 5 (0.226 g, 0.4 mmol, 5 mol%) in dry
toluene (20 mL), methylmagnesium bromide in diethyl
ether (3 M, 33 mL, 0.1 mmol, 1 mol%) was injected by
21
29
orthorhombic, Space group P2 2 2 , a=8.508 (2), b=
1
1 1
3
1
2
3.680 (6), c=15.876 A
,
, V=1847.9, Z=4 (11) A
98 K, v=0.823 mm , reflections collected 11922,
,
, T=
−
1
independent refections 3240 (Rint=0.0288), data/restrain-
syringe under N -atmosphere at room temperature. The
2
2
nts/parameter=3240/210/224, goodness of fit on F =
resulting solution was stirred for 30 min, a solution of
diethylzinc in toluene (1.0 M, 16 mL, 16 mmol) was then
injected by syringe, ensuring that the tip of the needle was
below the surface of the solution. The mixture was stirred
at room temperature for 45 min and a solution of the
appropriate aldehyde (8 mmol) in dry toluene (3 mL) was
added. The reaction was monitored by GC–MS and when
no more traces of the aldehyde were detected (20 h) the
reaction was quenched by slow addition of aqueous
1
.081, R =0.0170 [I>2|(I)] and wR =0.0460 (for all
1
2
data). The absolute structure parameter is −0.012 (9). For
compound 2 unit cell parameters were determined from a
least-squares fit of 75 accurately centered reflections
(
0
11.6<2q<25.0). Maximun D/|=0.003, maximun Dz=
−
3
.120 e A . Hydrogen atoms were included using the
,
rigid method for the methyl group and the others the
riding method, except the amine H, which was free.
CCDC 178737.
NH Cl solution (15%, 20 mL). The precipitated solid was
4
1
1
3. Bublitz, D. E. J. Organomet. Chem. 1970, 23, 225–229.
4. (a) Alberola, A.; Andr e´ s, C.; Pedrosa, R. Synlett 1990,
separated by filtration, air-dried and chromatographed
on a silica gel column (dichloromethane/hexanes 1:1) to
give 5 in almost quantitative yield. The filtrate was
extracted with diethyl ether (2×15 mL) and the combined
7
63–775; (b) Andr e´ s, C.; Nieto, J.; Pedrosa, R.; Villa-
ma n˜ an, N. J. Org. Chem. 1996, 61, 4130–4135.
2
0
15. Spectral data for compound 5: [h] =+66.3 (c 1.1,
organic layers were washed with brine, dried (MgSO ),
4
D
CHCl ), mp 157–160°C, IR (Nujol), 3351, 1604, 1562,
filtered and evaporated under reduced pressure. The
crude product was purified by bulb-to-bulb distillation or
flash column chromatography (EtOAc/hexanes 1:4) to
give the corresponding optically active secondary alcohol.
Chemical integrity was checked by H NMR, the enan-
tiomeric excess was determined by enantioselective
3
+
1
408, 1107, 1001, 831, 725. MS (EI), 567 (M , 2), 369
1
(20), 215 (12), 200 (32), 199 (100), 186 (14), 121 (55). H
NMR (CDCl , 300 MHz): 4.64–4.46 (m, 2H; Fc), 4.12 (s,
3
1
5
H; Cp), 3.97 (s, 5H; Cp), 3.84–3.58 (m, 6H; Fc), 3.48
3
3
(
td, 1H, J=9.9, J=3.6 Hz; H1), 3.16–3.04 (m, 4H;
2
2
×CH Fc), 1.94 (dm, 1H, J=11.7 Hz; H6 ), 1.88–1.04
HPLC.
2
eq
13
(m, 8H), 0.98 (s, 6H; 2×Me), 0.91 (s, 3H; Me-C5).
C
17. Dosa, P.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
445–446.
NMR (CDCl , 75 MHz): 72.16 (C1%), 70.27 (CH:Fc),
3